2. Background and Introduction
Cancer
Development of abnormal cells that divide uncontrollably which have
the ability to infiltrate and destroy normal body tissue
Chemotherapy
Use of anti-cancer (cytotoxic) drugs to destroy cancer cells.
Work by disrupting the growth of cancer cells
Nonspecificity
Toxicity
Adverse side effects
Poor solubility
3. Cancer Nanotechnology
interdisciplinary research, cutting across the disciplines of
Biology
Chemistry
Engineering
Physics
Medicine
Nanoparticles
Semiconductor quantum dots (QDs)
Iron oxide nanocrystals
Carbon nanotubes
Polymeric nanoparticles
Liposomes
Unique Properties
Structural
Optical
Magnetic
4. • Tumors generally can’t grow beyond 2 mm in size without
becoming angiogenic (attracting new capillaries) because
difficulty in obtaining oxygen and nutrients.
• Tumors produce angiogenic factors to form new capillary
structures.
• Tumors also need to recruit macromolecules from the blood
stream to form a new extracellular matrix.
• Permeability-enhancing factors such as VEGF (vascular
endothelial growth factor) are secreted to increase the
permeability of the tumor blood vessels.
5. Tissue selectivity
Tissues with a leaky endothelial wall contribute to a
significant uptake of NP. In liver, spleen and bone
marrow, NP uptake is also due to the macrophages
residing in the tissues.
6.
7. • In tumors the uptake of NP depends on the
so-called enhanced permeability and
retention effect (EPR).
9. Schematic of EPR (enhanced permeability
and retention) effect in solid tumors:
EPR, in principle, is based
on passive targeting
This passive targeting process facilitates tumor
tissue binding, followed by drug release for cell
killing.
Nanovehicles which fail to bind to tumor cells will
reside in the extracellular (interstitial) space, where
they eventually become destabilized because of
enzymatic and phagocytic attack. This results in
extracellular drug release for eventual diffusion to
nearby tumor cells and bystander cell.
10. How EPR works
1- nanovehicles passively target to vasculature
and extravasate through fenestrated tumor
vasculature.
2- the extended circulation time (stealth
features) allows accumulation in tumor tissue
3- lack of lymphatic drainage prevents removal
of nanoparticles after extravasation
11.
12.
13. DOXORUBICIN pharmacokinetics
In vivo distribution of long-circulating radiolabeled liposomes
i.v. injected into C26 tumour-bearing mice
CPILs: DPPC ( a saturated lipid)/ 20%GM1 ganglioside ( a stealth
Glycolipid)
18. Saturation of receptors affects the specificity of targeting.
Ruoslahti E et al. J Cell Biol doi:10.1083/jcb.200910104
19. Treating tumors with cooperative nanoparticles.
Targeting stressrelated protein,
p32, upregulated
upon thermal
treatment.
Ruoslahti E et al. J Cell Biol doi:10.1083/jcb.200910104
20. Molecular Cancer Imaging (QDs)
Tumor Targeting and Imaging
Emission wavelengths are size
tunable (2 nm-7 nm) 4
High molar extinction coefficients
Conjugation with copolymer
improves biocompatibility,
selectivity and decrease cellular
toxicity 5
size-tunable optical properties of ZnS-capped CdSe QDs
21. Correlated Optical and X-Ray Imaging
High resolution sensitivity in detection of small
tumors
x-rays provides detailed anatomical locations
Polymer-encapsulated QDs
No chemical or enzymatic degradations
QDs cleared from the body by slow filtration
or excretion out of the body
22. ANTICANCER DRUG
•Passive diffusion
•EPR
PHYSIOLOGICAL BARRIERS
non cellular based mechanisms
DRUG RESISTANCE
DRUG
cellular based mechanisms
•Endocytosis/phagocytosis
by the cells
DISTRIBUTION, CLEARANCE OF
•Overcome MDR
DRUG
Controlled tumoral interstitial
drug release
•Poorly vascolarized tumor
region
•Acidic
enviroments
in
tumors
•Biochemical alterations
•Large
volume
distribution
•Toxic side-effects
normal cells
of
on
23. TUMOR-TISSUE TARGETING
Conventional Nanoparticles
Long-circulating Nanoparticles
•
•
•
•
•
Size > 100 nm.
Delivery to RES tissues.
Rapid effect (0.5-3 hr).
For RES localized tumors
(hepatocarcinoma, hepatic metastasis,
non-small cell lung cancer, small cell
lung cancer, myeloma, lymphoma).
•
•
•
•
•
Size < 100 nm, “Stealth”, invisible to
macrophages.
Hydrophylic surface to reduce
opsonization (e.g. PEG)
Prolonged half-life in blood compartment.
Selective extravasation in pathological
site.
For tumors located outside the RES
regions.
Gradually absorbed by lymphatic system.
24. TUMOR-CELL TARGETING
MDR Reversion
A) Free doxorubicin enters into the
tumor cells by diffusion but is effluxed by
Pgp, resulting in the absence of
therapeutic efficacy.
B) Doxorubicin-loaded NPs adhere at the
tumor cell membrane where they release
their drug content, resulting in
microconcentration gradient of
doxorubicin at the cell membrane, which
could saturate Pgp and reverse MDR
Brigger et al., 2002
25. V di uscita
del farmaco(Attività Pgp)
Conc intracellulare farmaco
V di
ingresso
farmaco
Differenza di conc farmaco esterno/interno
27. Caelyx® is a form of doxorubicin| that is enclosed in liposomes.
It is sometimes known as pegylated doxorubicin hydrochloride
(PLDH). It is used to treat:
•Advanced ovarian cancer that has come back after being
treated with a platinum-based chemotherapy drug.
•Women with advanced breast cancer who have an increased
risk of heart damage from other chemotherapy drugs.
• Aids-related Kaposi’s sarcoma .
Myocet® , another form of liposomal doxorubicin, is used to
treat advanced (metastatic) breast cancer| in combination with
another chemotherapy drug, cyclophosphamide| .
29. Target: enzimi del rilassamento di DNA
Inibitori delle topoisomerasi
Doxorubicina
• Induce complesso ternario DNA-farmaco-Topoisomerasi
(filamenti di DNA rotti legati in 5’ a una tirosina
dell’enzima)
• Danneggia il filamento formando radicali liberi-
30.
31.
32.
33. Target: microtubuli
Antimitotici
inibizione di assemblaggio
stabilizzazione polimeri.
Microtubuli: polimeri di tubulina: crescita richiede GTP alle
estremita’ e sui monomeri.
Idrolisi di GTP a GDP disassembla microtubulo. Per la stabilità
servono MAP
